Abstract
Background:
Nonalcoholic fatty liver disease is inconsistently associated with ischemic stroke, with one study suggesting an association in women and not men. The relative importance of liver fibrosis, as opposed to fatty liver, for cardiovascular risk is increasingly appreciated. We hypothesized that advanced liver fibrosis is associated with incident ischemic stroke risk, and especially in women.
Methods:
We performed a case-cohort study in the REasons for Geographic and Racial Differences in Stroke cohort. Black and white individuals aged 45 and older were recruited between 2003 and 2007 and followed for ischemic stroke. The Fibrosis-4 (FIB-4) score and Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) were calculated using baseline data for stroke cases and a cohort random sample; advanced liver fibrosis was classified using validated cutoffs. Cox proportional hazards models were used to estimate hazard ratios (HR) of stroke after adjusting for potential confounders. Sex differences were assessed.
Results:
There were 572 incident ischemic strokes (285 in women) over 5.4 (SD, 2.2) years. Advanced liver fibrosis was not significantly associated with ischemic stroke overall using the FIB-4 (HR 1.44; 95% CI 0.49–4.28) or NFS (HR 1.76; 95% CI 0.67–4.61). However, liver fibrosis was associated with stroke in women (HR 3.51; 95% CI 1.00–12.34) but not men (HR 0.70, 95% CI 0.16–3.16) (P=0.098 for interaction) when using FIB-4. A similar but non-significant sex difference was seen for NFS.
Conclusion:
Advanced liver fibrosis may be associated with a higher risk of ischemic stroke in women but not men.
Keywords: Ischemic Stroke, Epidemiology, Liver Disease, NAFLD, Risk Factors, Women
Introduction
Chronic liver disease affects 20% of the population.(1) Histological liver fibrosis develops progressively along a continuum in most chronic liver diseases, and recent studies estimate a 5–9% prevalence of subclinical but histologically significant liver fibrosis in the general population without known liver disease.(2–4) Nonalcoholic fatty liver disease (NAFLD) is the most common underlying etiology, and viral hepatitis and alcoholic liver disease are additional causes.
It is increasingly evident that advanced liver fibrosis, and not isolated fatty liver per se, is independently associated with cardiovascular disease and mortality.(5–7) Liver fibrosis may also be associated with cerebrovascular disease. For example, a recent study suggested an association between liver fibrosis and ischemic stroke risk, but the study was inconclusive due to its cross-sectional, case-control study design with controls drawn from well patients.(8)
Additionally, the case-control study did not address sex differences, which have been reported in recent studies on the association between liver disease biomarkers and stroke risk.(9) For instance, a report from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study identified an association of baseline fatty liver biomarkers and future stroke in women but not men, though this study did not investigate the role of liver fibrosis.(9) A sex difference in the association between liver disease biomarkers and cerebrovascular disease was also supported by a study on cerebral white matter hyperintensities.(10)
Based on these data, we sought to further investigate the association between advanced liver fibrosis and ischemic stroke risk and sex differences therein, in a prospective study in which baseline measures of liver fibrosis were available. We hypothesized that advanced liver fibrosis, defined using serum-based indices, is associated with incident ischemic stroke risk, and particularly in women.
Methods
Study design
We performed a nested case-cohort study within REGARDS, a cohort study of 30,239 black and white participants recruited from 2003 to 2007 from the contiguous United States and followed prospectively for stroke (Supplemental Materials).(11,12) We used baseline data and blood samples of participants with incident ischemic stroke and a cohort random sample (CRS) of 1,104 participants selected in stratified groups by age groups, race, and sex. Liver function assays needed to compute liver fibrosis indices were performed in baseline blood samples for stroke cases and for the random cohort sample; the case-cohort design is an efficient one that precludes the need to measure laboratory markers in the entire cohort. Compared to a case-control study design, the case-cohort study design reduces selection bias because stroke cases and controls are sampled from the same prospective cohort sample. Further, the case-cohort study design allows for evaluation of person-time at risk. Participants contributed person-time until censored at the time of death or end of follow-up (September 1, 2011).
Participants provided verbal informed consent for telephone-based data collection and then provided written informed consent for further data collection during the home visit. Institutional review board approval was obtained from the participating institutions: University of Alabama at Birmingham, University of Vermont, University of Cincinnati, and Wake Forest University. The data used for this analysis can be made available to qualified investigators upon application to the REGARDS executive committee.
Population
The REGARDS participants included in this study were those with incident ischemic stroke and participants in the stratified CRS. We excluded participants with prior self-reported stroke at the time of baseline assessment, those with alcohol use greater than two drinks per day for men and greater than one drink per day for women, those missing alcohol use data, and those missing the baseline laboratory data required to calculate liver fibrosis indices (Figure 1). We excluded men with greater than two drinks per day and women with greater than one drink per day for the following reasons: first, significant alcohol use may cause abnormal liver enzymes and liver fibrosis scores unrelated to the presence of liver fibrosis; second, guidelines for metabolic liver disease recommend excluding people with significant alcohol use, for which the definitions are sex specific.(13–15) The data necessary for each index differed (see below), so there were two study samples of slightly different sizes. Specifically, albumin and platelet count were not measured in REGARDS until after several thousand participants were enrolled, after which these laboratory tests were performed for all consecutive participants. This was a frequent reason for exclusion from our study sample.
Figure 1. Participant flow diagram.
Necessary data differed by score, resulting in two slightly different study samples. At risk alcohol use was >2 drinks/day for men or >1 drink/day for women. Abbreviations: FIB-4, Fibrosis-4 Score; NFS, Nonalcoholic Fatty Liver Disease Fibrosis Score.
Measurements
Laboratory testing procedures and validity in REGARDS have been described.(16) We calculated two liver fibrosis indices for each participant: the Fibrosis-4 (FIB-4) score and the Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS).(17,18) These scores were calculated from baseline demographic variables, medical comorbidities, and laboratory data (Figure 2). We treated the indices as categorical variables by applying validated cutoffs for the detection of advanced liver fibrosis (F3 and F4 stage fibrosis). Because viral hepatitis data were unavailable in REGARDS and alcohol use can be underreported, and because these may be alternate causes of liver fibrosis in the REGARDS cohort in addition to NAFLD, we used the following cutoffs for FIB-4: >3.25, advanced liver fibrosis; <1.45, no fibrosis(19–21). These cutoffs were validated for use in viral hepatitis and alcoholic liver disease, and were also shown to be specific in the setting of NAFLD.(22–25) The NFS cutoffs were >0.676 for advanced liver fibrosis and <−1.455 for no liver fibrosis.(22) The outcome was incident ischemic stroke, ascertained using standard REGARDS procedures (Supplemental Material).
Figure 2. Formulae for liver fibrosis scores.
Fibrosis scores were the Fibrosis-4 score (FIB-4) and Nonalcoholic Fatty Liver Disease – Fibrosis Score (NFS).
Race, medical history, tobacco and alcohol use, and medications were self-reported. The following stroke risk factors were defined using standard REGARDS definitions (Supplemental Material): hypertension, diabetes, smoking, atrial fibrillation, and left ventricular hypertrophy. Aspirin, warfarin, and statin medication use were tabulated. Last, we considered baseline levels of factor VIII (FVIII), interleukin-6 (IL-6), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for post-hoc exploratory mediation analyses, given previously demonstrated associations between these biomarkers and stroke.(26–28)
Statistical Analyses
Standard descriptive statistics were used to compare the baseline characteristics of participants with and without advanced liver fibrosis, with weighting to account for stratification. The χ2 test with Yates correction was used to compare categorical variables, and linear regression for continuous variables. We used weighted Cox proportional hazards models to calculate hazard ratios (HR) with 95% confidence intervals (CI) for ischemic stroke by advanced liver fibrosis (presence versus absence).(11,26) We did not evaluate FIB-4 and NFS as continuous variables because they are not validated as linear correlates of histological liver fibrosis. Model 1 was adjusted for age, sex, and race. Model 2 was additionally adjusted for Framingham stroke risk factors: hypertension, systolic blood pressure, diabetes, current smoking, atrial fibrillation, left ventricular hypertrophy, and baseline cardiovascular disease. Model 3 was additionally adjusted for aspirin and warfarin use. All models were adjusted for an age*race interaction term because of prior evidence of such an interaction in REGARDS.(29) Because a prior REGARDS analysis demonstrated a sex interaction in the association between liver disease biomarkers and ischemic stroke, we performed a priori subgroup analyses stratified by sex and tested for effect modification by sex.(9,29) Interactions were defined as statistically significant on the multiplicative scale if the cross-product term p value was <0.10. In post-hoc exploratory analyses, we individually added FVIII, IL-6, and NT-proBNP to Model 2 to observe whether and to what extent these factors mediated the association between liver fibrosis and stroke. Mediation analyses were performed using a bootstrapping technique that generated 1,000 replicate samples to estimate the change (attenuation percentage with 95% CI) in the HR to Model 2 upon adding biomarkers. Mediation analyses were performed only for Model 2 after observing that the primary results of Model 2 were unchanged after adjusting for antithrombotic use in Model 3. In a post-hoc sensitivity analysis, FIB-4 was alternatively categorized using cutoffs (>2.67 and <1.3) used frequently in the setting of NAFLD.(30) Statistical analyses were performed using SAS 9.4 (Cary, NC). All analyses were two-tailed. The threshold of statistical significance allowed for an alpha error of 0.05.
Results
The study population included 572 participants with incident ischemic stroke and 1,104 participants in the stratified CRS. The median duration of follow-up was 5.4 (SD, 2.2) years. The mean age was 67.1 (SD, 11.7) years and 57% were women. Of the 572 participants with ischemic stroke, 285 were women. After exclusions, there were 844 total participants in the analysis using FIB-4 and 829 in the analysis using NFS (Figure 1). The mean FIB-4 and NFS scores were 1.65 (SD, 0.91) and −0.57 (SD, 1.42), respectively, which represent intermediate probabilities of liver fibrosis. The prevalence of advanced liver fibrosis in the cohort random sample was 5.1% by the FIB-4 score and 19.5% when defined by the NFS. Compared to participants without liver fibrosis, those with advanced liver fibrosis were older and had a generally higher burden of Framingham stroke risk factors and higher levels of FVIII, IL-6, and NT-proBNP (Table 1).
Table 1.
Baseline Characteristics,† Stratified by Fibrosis-4 Score and Nonalcoholic Fatty Liver Disease Fibrosis Scores in the Cohort Random Sample
| Characteristic | FIB-4>3.25 (n = 42) | FIB-4<1.45 (n = 421) | NFS>0.675 (n = 166) | NFS<−1.455 (n = 214) |
|---|---|---|---|---|
| Age, mean (SD) | 78 (9.6) | 61 (10.2) | 73 (10.1) | 59 (10.6) |
| Women | 23 (52) | 260 (62) | 102 (61) | 125 (58) |
| Race | ||||
| White | 23 (55) | 215 (51) | 73 (44) | 136 (64) |
| African American | 19 (45) | 206 (49) | 93 (56) | 78 (36) |
| Stroke belt resident | ||||
| Belt | 14 (33) | 165 (39) | 49 (30) | 78 (36) |
| Buckle | 11 (26) | 89 (21) | 47 (28) | 42 (20) |
| Non-belt | 17 (41) | 167 (40) | 70 (42) | 94 (44) |
| BMI, mean (SD), mg/kg | 25.3 (4.5) | 30.3 (6.9) | 32.3 (7.2) | 26.6 (5.3) |
| Waist, mean (SD), cm | 87 (17) | 96 (16) | 103 (14) | 88 (13) |
| SBP, mean (SD), mmHg | 130 (20) | 128 (17) | 134 (20) | 124 (17) |
| Hypertension | 27 (64) | 239 (57) | 126 (76) | 95 (44) |
| Diabetes | 9 (22) | 136 (31) | 104 (63) | 12 (6) |
| Hyperlipidemia | 8 (19) | 135 (32) | 64 (39) | 59 (28) |
| Atrial fibrillation | 4 (9) | 41 (9) | 18 (11) | 20 (9) |
| Cardiovascular disease | 10 (24) | 62 (14) | 46 (27) | 32 (15) |
| LVH | 3 (7) | 38 (9) | 23 (14) | 15 (7) |
| Current smoking | 1 (2) | 96 (23) | 19 (11) | 53 (25) |
| Aspirin use | 15 (36) | 161 (38) | 75 (45) | 78 (36) |
| Warfarin use | 2 (5) | 7 (2) | 7 (4) | 6 (3) |
| Statin use | 7 (17) | 122 (29) | 65 (39) | 52 (24) |
| FVIII, median (IQR), % | 130 (107–170) | 117 (94–145) | 126 (107–168) | 110 (91–137) |
| IL-6, mean (SD), pg/ml | 5.7 (4.0) | 4.0 (2.9) | 5.0 (3.0) | 3.6 (3.0) |
| BNP, median (IQR), pg/ml | 294 (134–615) | 62 (31–143) | 184 (83–477) | 51 (28–103) |
Abbreviations: FIB-4, Fibrosis-4 Score; NFS, Nonalcoholic Fatty Liver Disease Fibrosis Score; SD, standard deviation; LVH, left ventricular hypertrophy; FVIII, Factor VIII; IQR, interquartile range; IL-6, interleukin-6; BNP, N-terminal pro-B-type natriuretic peptide.
Data are reported as number (%) except as otherwise specified. Data are reported for the Cohort Random Sample so as to be representative of the REGARDS cohort. FIB-4>3.25 and NFS>0.675 represent a high probability of advanced fibrosis; FIB-4<1.45 and NFS<−1.455 represent a low probability.
Advanced liver fibrosis, defined by the FIB-4, was not associated with ischemic stroke (HR, 0.94; 95% CI, 0.80, 2.36) as compared to the absence of advanced liver fibrosis. Models adjusted for Framingham stroke risk factors and antithrombotic medication use also did not reveal an association (Table 2). However, there was a strong association in women and no association in men (p for interaction ≤ 0.1 in adjusted models). Specifically, the HR of ischemic stroke in women adjusting for risk factors was 3.45 (95% CI, 1.04, 11.47), and this was not attenuated after additional adjustment for antithrombotic medication use. When defined by the NFS, advanced liver fibrosis was not associated with ischemic stroke in unadjusted models (HR, 1.41; 95% CI 0.73, 2.74) or in multivariable models (Table 2). With regards to sex differences, a nominally similar, non-significant pattern was observed for the NFS; the effect estimate for ischemic stroke was greater for women than men in unadjusted and adjusted models, however this difference was not statistically significant in unadjusted models (P=0.17) or models adjusted for demographics and stroke risk factors (P=0.53) (Table 2). A similar pattern, albeit with non-significant hazard ratios, was observed in post-hoc sensitivity analyses using less specific FIB-4 cutoffs (Supplemental Materials).
Table 2.
Associations† between Advanced Liver Fibrosis and Ischemic Stroke
| Model 1 | Model 2 | Model 3 | |
|---|---|---|---|
| Fibrosis-4 Score (n=844; 273 cases, 571 controls) | |||
| All | 0.94 (0.8, 2.36) | 1.48 (0.50, 4.36) | 1.44 (0.49, 4.28) |
| Men | 0.54 (0.15, 1.96) | 0.74 (0.17, 3.27) | 0.70 (0.16, 3.16) |
| Women | 1.77 (0.57, 5.46) | 3.45 (1.04, 11.47) | 3.51 (1.00, 12.34) |
| P value for interaction | 0.16 | 0.10 | 0.098 |
| Nonalcoholic Fatty Liver Disease Fibrosis Score (n=829; 268 cases, 561 controls) | |||
| All | 1.41 (0.73, 2.74) | 1.80 (0.69, 4.68) | 1.76 (0.67, 4.61) |
| Men | 0.88 (0.33, 2.36) | 1.39 (0.39, 5.03) | 1.51 (0.43, 5.35) |
| Women | 1.97 (0.89, 4.36) | 2.10 (0.73, 6.02) | 1.93 (0.65, 5.79) |
| P value for interaction | 0.17 | 0.53 | 0.71 |
Results of Cox proportional hazards are reported as Hazard Ratio (95% confidence interval) for participants with a Fibrosis-4 Score >3.25 as compared to those with a score <1.45 and for participants with a Nonalcoholic Fatty Liver Disease Fibrosis Score >0.675 as compared to those with a score <−1.455. Model 1 is adjusted for age, sex, and race; Model 2 is additionally adjusted for Framingham stroke risk factors; Model 3 is additionally adjusted for aspirin and warfarin use. All models were adjusted for an age*race interaction term.
In mediation analyses, the addition of NT-proBNP to Model 2 partly attenuated the association between advanced liver fibrosis, defined by the FIB-4, and stroke among women (HR, 2.08; 95% CI, 0.60, 7.24). However, the addition of FVIII and IL-6 to Model 2 did not meaningfully attenuate the main effect association, and the attenuation percentage was not statistically significant for any of the biomarkers individually in bootstrapping analysis (data not shown).
Discussion
This prospective study provides new evidence that advanced liver fibrosis is associated with ischemic stroke risk in women but not men. Specifically, we extend a prior REGARDS report that found a sex difference in the association of fatty liver biomarkers with stroke in women but not men. Additionally, in this study, we found that the potent cardiovascular and stroke risk biomarker NT-proBNP may mediate some of this association.
We are not aware of other studies demonstrating an association between advanced liver fibrosis and stroke risk in a prospective, population-based cohort. A prior case-control study, including healthy patients undergoing well-health checks as the control group, found that an ultrasound-based measure of liver fibrosis was independently associated with ischemic stroke; differences by sex was not assessed.(8) The population-based nature of our study and the a priori stratification by sex are key differences in study design that may account for incongruous findings. Specifically, case-control studies with suboptimal control selection are prone to bias, so our results may be more representative of the true relationship between liver fibrosis and stroke. We found that advanced liver fibrosis, as defined by the FIB-4 score, was associated with an increased risk of ischemic stroke among only women. A similar, albeit not statistically significant, pattern was observed when using the NFS. Notably, the prevalence of advanced liver fibrosis as defined by the FIB-4 score in our cohort was similar to three population-based estimates of advanced liver fibrosis prevalence in addition to the prevalence seen in the prior case-control study.(2–4,8) In contrast, the prevalence of advanced liver fibrosis as defined by the NFS in our cohort was over twice these prior estimates, which suggests that this score may be less specific in the REGARDS cohort. This may account for the discrepancy between associations for FIB-4 and NFS. The difference in performance between the two scores may reflect our choice of FIB-4 cutoffs that are valid for multiple common liver diseases whereas the NFS is validated primarily for NAFLD. Using a more sensitive but less specific upper cutoff for FIB-4 in a sensitivity analysis produced results like those for NFS; the overall pattern of findings was consistent throughout.
Our results are consistent with a prior REGARDS analysis that investigated the association between the Fatty Liver Index, a validated NAFLD prediction score that does not assess presence of fibrosis, and ischemic stroke risk.(9) That study found that women with a Fatty Liver Index in the top decile were at an increased risk of stroke whereas this was not observed in men. Additionally, a single-center, cross-sectional study of Italian patients with and without NAFLD found that women over age 45 with advanced liver fibrosis had the highest prevalence of cerebral white matter hyperintensities on magnetic resonance imaging.(10) Taken together, these data suggest that advanced liver fibrosis may be a risk factor for ischemic stroke and other cerebrovascular sequelae, but only in women. One caveat is that individuals identified as having advanced liver fibrosis by the FIB-4 score in our study had lower BMI than expected; this suggests that these individuals perhaps had sarcopenia as a manifestation of advanced liver disease or had a lean form of metabolic liver disease. Confirmation of our findings with prospective liver disease phenotype ascertainment is critical.
Mechanisms for a possible association between liver fibrosis and ischemic stroke are several. Prior studies identified a dose-dependent association between liver fibrosis and cerebral microhemorrhages and white matter lesions, which may reflect the presence of small vessel disease.(31,32) Additionally, NAFLD, in particular when accompanied by fibrosis, is associated with systemic inflammation and vascular inflammation.(32–34) Inflammatory mechanisms in liver disease may increase the risk of stroke through increased atherosclerosis, including of the carotid artery.(35–39) However, we did not observe mediation of our findings with adjustment for IL-6, a pro-inflammatory cytokine and strong stroke risk factor in REGARDS.(28) Advanced liver disease is also associated with a mixed coagulopathy and a pro-thrombotic state, which could increase the risk of ischemic stroke.(40) We did not see mediation of the association of liver fibrosis with stroke after adjustment for FVIII, but FVIII is not a good marker of liver disease-related coagulopathy. Last, the presence of mediation, albeit not statistically significant, by NT-proBNP suggests a pathophysiologic connection between liver fibrosis and atrial cardiopathy, atrial fibrillation, or other factors related to NT-proBNP levels. Indeed, cirrhosis and nonalcoholic steatohepatitis – both forms of liver disease with advanced fibrosis – were recently found to be associated with an increased risk of atrial fibrillation.(41,42) It should be noted that smoking was less common in those with advanced liver fibrosis in our analysis, suggesting that lifestyle factors alone did not drive the observed associations. We did not find evidence of mediation by inflammatory cytokine IL-6. However, even though NAFLD is more prevalent in patients with cardiovascular risk factors, the association of NAFLD and cardiovascular disease may be in part independent of these risk factors and instead due to inflammatory changes that we did not investigate.
With respect to the sex differences we observed, this may be explained by sex and age interactions in the severity of liver fibrosis in NAFLD. Post-menopausal women are at an increased risk of more advanced fibrosis, and it is postulated that the loss of a protective effect of estrogen is responsible.(43,44) This may compound changes in cardiovascular disease risk and risk factors that coincide with the menopausal transition.(45) An alternate explanation is that exclusion based on alcohol use were sex specific; however, the exclusion of women who drank greater than one drink per day is a conservative bias because it increases confidence that the observed association in women was unlikely related to the effect of alcohol consumption on liver enzymes. A second alternate explanation is confounding by age. Age is an important risk factor for ischemic stroke, and the fibrosis scores are derived in part from age. Although we adjusted models for age, it remains possible that the influence of age is in part responsible for our results. Were this the case, we would not necessarily expect to find sex differences because we would expect confounding by age to be an issue irrespective of sex. Regardless, it is critical that future studies use more precise liver disease measures such as transient elastography,(46) that are independent of age, in a large prospective cohort to confirm our findings and to understand underlying mechanisms.
The strengths of this study are the use of an efficient case-cohort study design using data from a national, prospective cohort study and the pre-specified evaluation of sex differences that extends prior findings fatty liver disease from REGARDS. There are also several important limitations. First, liver fibrosis indices are surrogate markers. While validated, they are not a substitute for direct measures of liver fibrosis such as biopsy. However, liver biopsy is impractical for large cohort studies like REGARDS, which also have great strengths in terms of the large numbers of outcomes not otherwise available in smaller prospective studies. The performance of the FIB-4 appeared to be reliable in our cohort based on its agreement with other correlates of liver fibrosis in the general population.(2–4) In contrast, the NFS appeared to be less reliable given that the prevalence of fibrosis in our study sample based on the NFS was at least twice that observed in other studies. This may account for discrepant results when using the FIB-4 and NFS. Second, there were too few participants with hemorrhagic strokes to model, so our analyses do not contribute to the understanding of liver disease as a hemorrhagic stroke risk factor. Finally, residual confounding is always possible in epidemiological studies since confounders may be unaccounted for or misclassified. Analyses using FIB-4 mitigated some of this risk because it was validated in liver conditions that were not measured in the sample. In light of limitations, our hypothesis-generating findings require confirmation using additional liver measures before clinical applications can be considered.
Conclusions
Advanced liver fibrosis as defined by the FIB-4 score was associated with an increased risk of ischemic stroke among women but not men, similar to prior findings on fatty liver disease. Confirmation of our findings and mechanistic investigation is warranted.
Supplementary Material
Acknowledgements:
This research project is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIA. Representatives of the NINDS were involved in the review of the manuscript but were not directly involved in the collection, management, analysis or interpretation of the data. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at: https://www.uab.edu/soph/regardsstudy/. Additional funding was provided by K08HL096841, which included funding for select assays.
Sources of Funding:
NSP: National Institute of Neurological Disorders and Stroke (NINDS) T32NS07153 (PI: Elkind). IK: NIH (U01NS41588). LVW: NIH (K23HL136891). MSVE: NIH (R01NS029993). NZ: NIH (U01NS41588). MC: NIH (U01NS41588). REGARDS: NIH (U01NS041588, K08HL096841)
Footnotes
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Conflicts of Interest: None.
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